化学
激酶
坦克结合激酶1
IκB激酶
立体化学
生物化学
细胞周期蛋白依赖激酶2
NF-κB
信号转导
蛋白激酶A
作者
Jeffrey W. Johannes,Claudio Chuaqui,Scott D. Cowen,Erik Devereaux,Lakshmaiah Gingipalli,Audrey Molina,Tao Wang,David Whitston,Xia Wu,Haijun Zhang,Michael Zinda
标识
DOI:10.1016/j.bmcl.2013.12.123
摘要
The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-ε is described. Various internal azabenzimidazole leads and reported TBK1/IKK-ε inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-ε. This screen resulted in initial hit compound 3. The TBK1/IKK-ε enzyme and cell potency of this compound was further improved using structure guided drug design. Systematic exploration of the C6 aryl group led to compound 19, a potent inhibitor of TBK1 with selectivity against cell cycle kinases CDK2 and Aurora B. Further elaboration and optimization gave compound 25, a single digit nM inhibitor of TBK1. These compounds may serve as in vitro probes to evaluate TBK1/IKK-ε as an oncology target.
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